1-Amino naphthyridines

ABSTRACT

This invention relates to 1-amino naphthyridines prepared by a base-catalyzed condensation while in an aprotic solvent. In this condensation an o-alkyl aryl nitrile may be reacted either with the same or different o-alkyl aryl nitrile or with another nitrile. The -amino naphthyridines are useful an antifungal and antibacterial agents.

Field of smhIII...I6/% N, 294.8 R, 295 s t v United States Patent [.191Mayer et al [45] Dec. 23, 1975 1 l-AMINO NAPHTHYRIDINES [75] Inventors:Joseph Mayer, New York, N.Y.; {56] References cued Margaret R. Sherlock,Bloomfield, UNITED STATES PATENTS NJ. 3,842,087 l0/l974 Williams et260/295 N 73 ASS Sche t K '1 I gnee mg corporation em worth PrimaryExaminer-Alan L. Rotrnan Attorney, Agent, or Firm-Stephen B. Coan;Raymond [22] Filed: July 16, 1973 A. McDonald [2] Appl. No.: 379,525[57] AB CT MM Application Data This invention relates to l-aminonaphthyridines pre- [63] Con'l'lmlalbfi-ili-Pim f 7 N pared by abase-catalyzed condensation while in an I i' 'g;;g' wh'ch a of aproticsolvent. in this condensation an o-alkyl aryl 1971' abandomd' nitrilemay be reacted either with the same or different o-alkyl aryl nitrile orwith another nitrile. The [52] CL g 3 3 1 -amino naphthyridines areuseful an antifungal and an- 424/251'; 424/263 [51] Int. C|. C071)213/74 7 Claims, No Drawings 1 l-AMINO NAPHTHYRIDINES This applicationis a continuation-impart application of our copending application, Ser.No. 816,075, filed Apr. 14, 1969, now abandoned, which application inturn, is a continuation-in-part application of our copending applicationSer. No. 119,377, filed Feb. 26, 1971 now abandoned.

This invention relates to novel compositions of matter which maygenerically be described as l-amino 3-substituted naphthyridines, toprocesses for their preparation and to their applied use characteristicsas antibacterial and antifungal agents.

More particularly, this invention, in its composition of matter aspect,relates to l-amino-2,5-naphthyridines, to l-amino-2,6-naphthyridines,l-amino-2,7- naphthrydines, to S-amino-l,7-naphthyridines, each of saidgroups of naphthyridines being further substituted with suchsubstituents as lower alkyl, phenyl, benzyl, phenethyl, pyridyl,thienyl, furyl, pyrazinyl and pyrimidyl radicals.

In its process aspects this invention relates to the base-catalyzedcondensation of an ortho-alkyl aryl nitrile either with itself or withanother appropriate nitrile, said condensation taking place in anaprotic solvent.

In another of its process aspects, this invention relates to theapplication of the compositions of matter of this invention asantibacterial agents, said agents being utilized preferably in the formof the pharmaceutical formulations prepared consistent with skills wellknown and practiced by pharmaceutical artisans.

In another of its aspects, this invention relates to the application ofthe compositions of this invention as antifungal agents, said agentsbeing utilized preferably in the form of pharmaceutical formulationsprepared consistent with skills well known by pharmaceutical artisans.

The compositions of matter of this invention may generically be depictedas naphthyridines having the structural formula:

wherein R represents lower alkyl, phenyl, benzyl, *phenethyl, thienyl,furyl, pyrazinyl, pyrimidyl, or pyridyl, R represents hydrogen, loweralkyl, phenyl, benzyl, phenethyl and pyridyl, and B, together with thecarbon atoms to which it is attached, is a pyrido moiety. Moreconveniently, the naphthyridines may also be depicted by the followingstructural formulae:

H2 rin N N/\ R" 1 K/ Z NH2 wherein R and R are as defined for I, saidstructures la, lb, lo, and Id being S-amino-1,7-naphthyridine, 1- amino2,7-naphthyridines, l-amino-2,6-naphthyridines, and1-amino-2,S-naphthyridines, respectively.

Here, and elsewhere through this specification it will be understoodthat the phenyl, benzyl, thienyl, furyl, phenethyl, pyrazinyl,pyrimidinyl and pyridyl substituents. as well as the pyrido moieties ofthe naphthyridine ring structures, can bear such other substituents aswould occur to a skilled organic chemist. Solely for illustration andwithout limitation, such substituents include lower alkyl, lower alkoxy,halo (chloro, bromo, iodo) nitro, lower alkylmercapto, trifluoromethyland di(loweralkyl)amino and the like.

As used throughout this specification, the term lower alkyl" means alkylradicals having from 1 to 6 carbon atoms which can be arranged asstraight or branched chains, and among which are, for purposes ofillustration but without limiting the generality of the foregoing,methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl and n-hexyl.

The process aspect of this invention is carried out by condensing theappropriate reactants in the presence of a base which is in an atropicnon-reactive solvent at temperatures of about C to about C. Morespecifically, the process for preparing the compounds of this inventionis essentially comprised of the condensation of an ortho-alkylarylnitrile either with the same or different ortho-alkyl arylnitrile orwith another type organic nitrile. in effecting the condensation thereactants are brought into contact with each other in the presence of abase; preferably, the reaction taking place in a solvent. In general,any atropic non-reacting solvent is suitable and such solvents includehydrocarbons, halohydrocarbons, tertiary amines, ammonia, ethers,tertiary amides, nitriles and the like, satisfying the requirements thatthey be liquid at reaction temperatures. Preferred solvents aredimethylformamide, dimethylsulfoxide, tetramethylurea, hexamethylphosphoramide, dioxane, tetrahydrofuran, dimethoxyethane, ether liquidammonia, benzene, toluene and xylene. The bases generally found suitablefor this reaction are the commonly used strong bases for alkylationreactions and include, potassium, t-butoxide, sodium t-amylate, sodium2-methyl-2-butoxide, alkali metal amides such as sodium amide, potassiumamide, lithium diethylamide, lithium diisopropylamide, sodium hydride,lithium hydride, triphenylmethyl lithium, tri phenylmethyl sodium,naphthalene sodium and triphenylmethyl potassium. In general, thereactants are stirred together at temperatures in the range of about 60to about 80C, this temperature, of course, being dependent upon thesolvent and speed of reaction desired. Preferably the reactiontemperature is about C although more specificreactant/solvent/temperaturelcombination factors are described in theworking examples set forth hereinbelow.

The nature of the general chemical reaction involved as well as of thegeneral nature of the compounds fomied may be illustrated as follows:

wherein B, R and R are as previously defined.

From the foregoing reaction scheme it becomes obvious that the secondcyano molecule (IV) participating in the reaction (i.e. R CN) can eitherbe identical with 30 BRO/H (I P It is also obvious from the reactionscheme that when different ortho-alkyl aryl nitriles are condensed, fourdifferent products may result therefrom. Such products may berepresented as follows:

VII II NH VIII 2 CHZRZ 2 CHQRZ f H232 'l' L A j A b /N c/ NR NH; 2

IX X XI the ortho-alkyl aryl nitrile (ll) molecule or different 50 fromit. In the first case the general structure of the product will be asfollows:

wherein R,. R and B are as previously described and A is a pyridylradical. in the second situation wherein the reactants are different,i.e. ll and R CN are not the same. the general structure of the reactionproduct is as ,5 given for formula I. In the latter situationcondensation between two molecules of the first component (II) can alsotake place as a side reaction. In such situations separation of thedesired product may be accomplished by standard techniques such asfractional crystallization and column chromatographic techniques.

wherein the 0" and O moieties represent different pyrido formations andR is as defined in formula 1. Again, in such situations separation ofthe desired product may be accomplished by standard techniques such asfractional crystallization and column chromatographic techniques.Representative of the organic nitriles (lV) suitable for reaction withthe o-alkyl aryl nitriles of formula II are such compounds as 2-cyanopyridine, 3-cyanopyridine, 4-cyanopyridine, benzonitrile, o, m andp methoxy benzonitrile, 2,3- 2,6' 3,4- and 3,5- dimethoxybenzonitrile,3,4-methylenedioxyphenyl acetonitrile, o, m and p chlorobenzonitrile,trifluoromethyl benzonitrile, land Z-naphthonitrile, benzylcyanide, o, mand p chlorobenzyl cyanide, o, m and p methylbenzyl cyanide, homoveratronitrile, 4- methoxybenzyl cyanide, 2-cyano thiophene 2- and 3- thiopheneacetonitrile. Z-cyanofurane, cyclobutyl cyanide, cyclopentyl cyanide,cyclohexyl cyanide and the like.

The following examples will further illustrate the process aspects forproducing the tangible embodiments of the compounds of this invention.

5 EXAMPLE I Preparation of l-amino-2,5-naphthyridines 1-Amino-3(2-methyl-3-pyridyl )-2,5-naphthyridine To 5.9 g. of3-cyano-2-methylpyridine dissolved in 30 ml. of dimethylformamide,gradually add 6.7 g. of potassium t-butoxide at about 5C. Maintain themixture at 5C for 4-6 hours and quench the reaction in ice water.Collect the crystalline precipitate and recrystallize from toluene toyield l-amino-3(2-methyl-3- pyridyl)-2,5-naphthyridine.

In a similar manner by substituting the 3-cyano-2- methylpyridine withequivalent quantities of 3-cyano- 2-ethylpyridine,3-cyano-2-benzylpyridine, 3-cyano-2- phenethylpyridine and 3--cyano-2-phenylproylpyridine and by substantially following theprocedure of this example there is produced l-amino-3(2-ethyl-3- pyridyl)-4-methyl-2,5-naphthyridine; l -amino-3-(2- benzyl-3-pyridyl)-4-phenyl-2,S-naphthyridine; lamino-3-(2-phenethyl-3-pyridyl)-4-benzyl-2,5-naphthyridine;1-amino-3-(2-phenylpropyl-3-pyridyl)-4- phenethyl-2,S-naphthyridine,respectively. Similarly, in those instances wherein it is desired toproduce those compounds bearing substituents on the pyridyl, phenyl andbenzyl moieties of the foregoing then, as expected, the appropriatelysubstituted starting reactants are then similarly reacted.

EXAMPLE ll 1-Amino-3-methyl-2,5-naphthyridine To 6.7 g. of potassiumt-butoxide in dimethylformamide at -5C add, in a portionwise fashion,5.9 g. of 3-cyano-2-methylpyridine and stir the reaction mixture for 1hour. Add, in a portionwise fashion, 10.2 g. of acetonitrile and stirthe reaction mixture at 0-5C for 48 hours. Quench the reaction in icewater, filter the precipitate and recrystallize the desired l-amino-3-methyl-2,5naphthyridine from toluene.

[n a similar manner by substituting the acetonitrile of the foregoingreaction with equivalent quantities of benzonitrile, benzylcyanide,phenpropionitrile, propio nitrile. 2-cyanopyridine, 3-cyanopyridine,4-cyanopyridine, 2-methoxybenzonitrile, 3-methoxybenzonitrile,4-methoxybenzonitrile, 2,3-dimethoxybenzonitrile,2,6-dimethoxybenzonitrile, 3,4-methylenedioxybenzonitrile,2-chlorobenzonitrile, 3-chlorobenzonitrile, 4-chlorobenzonitrile,2-trifluorobenzonitrile, 3-trifluorobenzonitrile,4-trifluorobenzonitrile, l-naphthonitrile, Z-naphtonitrile,2-chlorobenzylcyanide, 3- chlorobenzylcyanide, 4-chlorobenzylcyanide, 2-methylbenzylcyanide, S-methylbenzylcyanide and 4- methylbenzylcyanide,4-methoxybenzylcyanide, 2- cyanothiophene. 2-thiopheneacetonitrile,3-thiopheneacetonitrile, 2-cyanofuran, cyclobutylcyanide,cyclopentylcyanide, cyclohexylcyanide, 2- cyanopyrimidine,S-cyanopyrimidine, 2-cyanopyrazine and by substantially following theforegoing reaction procedure there is produced l-amino-3 -phenyl-2,5-naphthyridine, l-amino-3-benzyl-2,5-naphthyridine,l-amino-3-phenethyl-2,5-naphthyridine, 1-amino-3-ethyl-2,5-naphthyridine, l-amino-3-(2-pyridyl)-2,5- naphthyridine,l-amino-3-( 3-pyridyl)-2,5-naphthyridine,l-amino-3-(4-pyridyl)-2,5-naphthyridine, lamino-3-( 2-methoxyphenyl)-2,5-naphthyridine, lamino-3-( 3-methoxyphenyl )-2,5-naphthyridine,lamino-3-(4-methoxyphenyl)-2,5-naphthyridine, lamino-3-(2.3-dimethoxyphenyl )-2,5-naphthyridine,

5 amino-3-(4-chlorophenyl)-2,5-naphthyridine,

6 1-amino-3-(2,6-dimethoxyphenyl)-2,5-naphthyridine, l-amino- 3-(3,4-methylenedioxyphenyl )-2,5-naphthyridine, l-amino-3-( 2-chlorophenyl)-2,5-naphthyridine, l-amino-3-( 3-chlorphenyl )-2,5-naphthyridine, l

1- amino-3-( 2-trifluoromethylphenyl )-2,5 -naphthyridine, l-amino- 3-(3-trifluoromethylphenyl )-2,S-naphthyridine, l-amino-3-(4-trifluoromethylphenyl )-2,5-naphthyridine,l-amino-3-(oz-naphthyl)-2,5-naphthyridine, l-amino-3-( B-naphthyl)-2,5-naphthyridine, l-amino-3- (2-chlorobenzyl )-2,5-naphthyridine,l-amino-3-( 3- chlorobenzyl)-2,5-naphthyridine, l-amino-3-(4-chlorobenzyl )-2,5-naphthyridine, 1-amino-3-( 2-methylbenzyl)-2,5-naphthyridine, l-amino-3-( 3-methylbenzyl 2,5-naphthyridine,l-amino-3-(4-methylbenzyl)-2,5- naphthyridine, l-amino-3-(4-methoxybenzyl )-2,5- naphthyridine, l-amino-3-( 2-thienyl)-2,5-naphthyridine, 1-amino-3-( Z-thienylmethyl )-2,5-naphthyridine,l-amino-3-( B-thienylmethyl )-2,5-naphthyridine, lamino-3-( 2-furyl)-2,5-naphthyridine, l-amino-3- cyclobutyl-2,S-naphthyridine,l-amino-3-cyclopentyl- 2,5-naphthyridine,l-amino-3-cyclohexyl-2,S-naphthyridine,l-amino-3-(2-pyrimidinyl)-2,5-naphthyridine,l-amino-3-(3-pyrimidinyl)-2,5-naphthyridine, l -amino-3-( 2-pyraziny1)-2,S-naphthyridine.

Similarly, by substituting the 3-cyano-2-methylpyridine reactant withequivalent quantities of 3-cyano-2- ethylpyridine,3-cyano-2-benzylpyridine, 3-cyano-2- phenethylpyridine and bysubstantially following the foregoing reaction procedure there isproduced 1- amino-3,4-dimethyl-2,5naphthyridine, 1-amino-3-methyl-4-phenyl-2,5-naphthyridine, l-amino-3-methyl-4-benzyl-2,S-naphthyridine, respectively. Similarly, in each of thosereactions wherein the 3-cyano-2-methylpyridine has been substituted withanother 3-cyano-2- substituted pyridine the acetonitrile reactant mayalso be substituted with the aforementioned nitriles and bysubstantially following the procedure described in the example, there isproduced the appropriate l-amino-3 and 4-substituted,2,5-naphthyridines.

EXAMPLE lll Preparation of l-Amino-2,6-Naphthyridines.

l-Amino-3-( 3-methyl-4-pyridyl )-2,6-naphthyridine To 5.9 g. of4-cyano-3-methylpyridine dissolved in 30 ml. of dimethylformamide,gradually add 6.7 g. of potassium t-butoxide at about 5C. Maintain themixture at 5C for 4-6 hours and quench the reaction in ice water.Collect the crystalline precipitate and recrystallize from toluene toyield l-amino-3-(3-methyl-4- pyridyl )-2,6-naphthyridine.

In a similar manner by substituting the 4-cyano-3- methylpyridine withequivalent quantities of 4-cyano- 3-ethylpyridine,4-cyano-3-benzylpyridine, 4-cyano-3- phenethylpyridine and4-cyano-3-phenylpropylpyridine and by substantially following theprocedure of this example there is produced 1-amino-3-(3-ethyl-4-pyridyl )-4-methyl-2,6-naphthyridine, l-amino-3-( 3- benzyl-4-pyridyl)-4-phenyl-2,o'naphthyridine, l amino-3-( 3-phenethyl-4-pyridyl)-4-benzyl-2,6-naphthyridine, l-amino-3-( 3phenylpropyl-4 -pyridyl )-4-phenethyl-2,6-naphthyridine, respectively. Similarly, in those instanceswherein it is desired to produce those compounds bearing substituents onthe pyridyl, phenyl or benzyl moieties of the foregoing then. asexpected, the appropriately substituted starting reactants are thenreacted according to the procedure set forth in this example.

7 EXAMPLE 1v l-Amino-3-methyl-2,b-naphthyridine To 6.7 g. of potassiumt-butoxide in dimethylformamide at -5C add. in a portionwise fashion.5.9 g. of 4cyano3methylpyridine and stir the reaction mixture for 1hour. Add. in a portionwise fashion. 10.2 g. of acetonitrile and stirthe reaction mixture at 05C for 48 hours. Quench the reaction in icewater, filter the precipitate and recrystallize the desired l-amino-3-methyl-2,b-naphthyridine.

In a similar manner by substituting the acetonitrile of the foregoingreaction with equivalent quantities of benzonitrile, benzylcyanide,phenpropionitrile, propionitrile, Z-cyanopyridine, 3-cyanopyridine.4-cyanopyridine, 2-methoxybenzonitrile, 3-methoxybenzonitrile,4-methoxybenzonitrile, 2,3-dimethoxybenzonitrile,2,6dimethoxybenzonitrile, 3,4-methylenedioxybenzonitrile,2-chlorobenzonitrile, 3-chlorobenzonitrile, 4-chlorobenzonitrile.Z-trifluorobenzonitrile, 3trifluorobenzonitrile,4-trifluorobenzonitrile. l-naphtonitrile, Z-naphtonitrile,2-chlorobenzylcyanide, 3- chlorobenzylcyanide, 4-chlorobenzylcyanide. 2-methylbenzylcyanide, 3-methylbenzylcyanide and 4- methylbenzylcyanide,4-rnethoxybenzylcyanide, 2- cyanothiophene, Z-thiopheneacetonitrile,3-thiopheneacetonitrile, 2-cyanofuran, cyclobutylcyanide,cyclopentylcyanide, cyclohexylcyanide, 2- cyanopyrimidine,S-cyanopyrimidine, Z-cyanopyrazine and by substantially following theforegoing reaction procedure there is produced 1-amino-3-phenyl-2,6-naphthyridine, lamino-3benz vl2 ,6-naphthyridine, l-amino-3-phenethyl-2,6-naphthyridine, l-amino- 3- ethyl-2,6- naphthyridine,l-amino-3-( 2-pyridyl )-2,6- naphthyridine,l-amino-3-(3-pyridyl)-2,6-naphthyridine.lamino-3-(4-pyridyl)-2.6-naphthyridine, l amino-3-( 2-methoxyphenyl)-2,6-naphthyridine. lamino-3-( 3-methoxyphenyl )-2,6-naphthyridine,lamino-3-( 4-methoxyphenyl )-2,6-naphthyridine, lamino-3-(2,3-dimethoxyphenyl)-2,6 naphthyridine, l-amino- 3-( 2.6-dimethoxyphenyl)-2,6-naphthyridine, l-amino- 3-( 3 ,4-methylenedioxyphenyl)-2,6-naphthyridine, l-amino-3-( 2-chlorphenyl)-2,6-naphthyridine,-naphthyridine, lamino-3-(3-chlorphenyl)-2,6-naphthyridine,l-amino-3(4-chlorphenyl)-2,6-naphthyridine.1-amino-3-(2-trifluoromethylphenyl)-2,6-naphthyridine lamino-33-trifluoromethylphenyl )-2,6- naphthyridine, 1-amino-3-(4-trifluoromethylpheny] 2,6-naphthyridine,l-amino-3-(a-naphthyl)-2,6-naphthyridine, l-amino-IH B-naphthyl)-2,6-naphthyridine, l-amino- 3-( 2-chlorobenzyl )-2,6-naphthyridine,lamino-3-( 3-chlorobenzyl )-2,6-naphthyridine, l-amino-3-(4-chlorobenzyl )-2,6-naphthyridine, l-amino-3-( 2- methylbe nzyl )-2,6-naphthyridine, l-amino-3-( 3- methylbe nzyl )-2,6-naphthyridine,l-amino- 3-(4- methylbenzyl )-2,6-naphthyridine, l-amino-3-(4-methoxybenzyl )-2,6-naphthyridine, l-amino-3 2- thienyl)-2,5-naphthyridine. 1-amino-3-(2-thienylmethyl )-2,6-naphthyridine,l-amino-3-( 3-thienylmethyl 2,6-napthyridine,l-amino-3-(2-furyl)-2,6naphthyridine.l-amino-3-cyclobutyl-2,o-naphthyridine,lamino-3-cyclopentyl-2,6-naphthyridine, l-aminol 3-cyclohexyl-2,6-naphthyridine, l-amino-3-( 2- pyrimidinyl)-2,6-naphthyridine, l-amino-3-( 3- pyrimidinyl )-2,6-naphthyridine,l-amino-3-( 2- pyrazinyl )-2.6naphthyridine.

Also by substituting the 4-cyano-3-methylpyridine with equivalentquantities of 4-cyano-3-ethylpyridine,

8 4-cyano-3-benzylpyridine. 4-cyano-3-propylpyridine,4-cyano-3-phenethylpyridine, 4cyano-3-phenylpropylpyridine and bysubstantially following the foregoing reaction procedure there isproduced l-amino-3,4- dimethyl-2.6-naphthyridine,l-amino-3-methyl-4-phenyl-2,6-naphthyridine,l-amino-3-methyl-4-benzyl-2,6- naphthyridine.l-amino-3-methyl-4-phenethyl-2,6- naphthyridine, respectively. Also ineach of those reactions wherein the 4cyano-3-methylpyridine has beensubstituted with another 4-cyano-3-substituted pyridine, theacetonitrile reactant may also be substituted with the aforementionednitriles and by substantially following the procedure described in thisexample there is produced the appropriately l-amino-3 and 4- substituted2,6-naphthyridines.

Preparation of l-amino2.7-naphthyridines EXAMPLE V 1-Amino-3-(4-methyl-3-pyridyl )-2,7-naphthyridines To 3 g. of3-cyano-4-methylpyridine dissolved in 30 ml. of dimethylformamide,gradually add 3.4 g. of potassium t-butoxide at about 5C over a periodof 20 minutes. Maintain the reaction at 5C and then at 2025C for anotherl2 hours. Quench the reaction in ice water, collect the precipitate andrecrystallize from ethanol-hexane to yield l-amino-3-(4-methyl-3-pyridyl)-2,7-naphthyridine, m.p. 280282C.

In a similar manner by substituting the 3-cyano-4- methylpyridine withequivalent quantities of 3-cyano- 4'ethylpyridine,3-cyano-4-benzylpyridine, 3-cyano-4- phenethylpyridine and3-cyano-4-phenylpropylpyridine and by substantially following theprocedure of this example there is produced lamino-3-(4-ethyl-3- pyridyl)-4-methyl-2,7-naphthyridine, l-amino-3-( 4- phenethyl-3-pyridyl)-4-phenyl-2,7-naphthyridine;lamino-3-(4phenethyl-3-pyridyl)-4-benzyl-2,7-naphthyridine;l-amino-3-(4-phenylpropyl-3-pyridyl)-4- phenethyl-2,7-naphthyridine,respectively. Similarly, in those instances wherein it is desired toproduce those compounds bearing substituents on the pyrido, pyridyl,phenyl and benzyl moieties of the foregoing then, as expected, theappropriately substituted starting reactants are then similarly reacted.

EXAMPLE Vl l-Amino-3-methyl-2,7-naphthyridine To 6.7 g. of potassiumt-butoxide in dimethylformamide at 05C add, in a portionwise fashion,5.9 g. of 3-cyano-4-methylpyridine and stir the reaction mixture for lhour. Add, in a portionwise fashion, l().2 g. of acetonitrile and stirthe reaction mixture at 0-5C for 48 hours. Quench the reaction in icewater, filter and precipitate and recrystallize the desired l-amino-3-methyl-2,7-naphthyridine from toluene.

[n a similar manner by substituting the acetonitrile of the foregoingreaction with equivalent quantities of benzonitrile, benzylcyanide,phenpropionitrile, propionitrile, Z-cyanopyridine, 3-cyanopyridine,4-cyanopyridine, 2-methoxybenzonitrile, 3-methoxybenzonitrile,4-methoxybenzonitrile, 2,S-dimethoxybenzonitrile,2,6-dimethoxybenzonitrile, 3,4-methylenedioxybenzonitrile,2-chlorobenzonitrile, 3-chlorobenzonitrile, 4-chlorobenzonitrile,Z-trifluorobenzonitrile, 3-trimethylbenzylcyanide, B-methylbenzylcyanideand 4- 9 methylbenzylcyanide, 4-methoxybenzylcyanide, 2- cyanothiophene,Z-thitiphencacetonitrile, 3-thiopheneacetonitrile, Z-Cyanofuran,cyclobutylcyanide, cyclopentylcyanide, cyclohexylcyanide. 2-cyanopyrimidine, -cyanopyrimidine, 2-cyanopyrazine and by substantiallyfollowing the foregoing reaction procedure there is producedl-amino-3-phenyl-2,7- naphthyridine, 1-amino-3-benzyl-2,7-naphthyridine,l-amino-3-phenethyl-2,7-naphthyridine, l-amino-3- ethyl-2,7-naphthyridine, 1-amino-3-(2-pyridyl)-2,7- naphthyridine,1-amino-3-(3-pyridyl)-2,7-naphthyridine,l-amino-3-(4-pyridyl)-2,7-naphthyridine, lamino-3-( 2-methoxyphenyl)-2,7-naphthyridine, 1- amino-3( 3-methoxyphenyl )-2,7-naphthyridine, 1-amino-3-(4-methoxyphenyl)-2,7-naphthyridine,lamino-3-(2,3-dimethoxyphenyl)-2,7-naphthyridine,1-amino-3-(2,6-dimethoxyphenyl)-2,7-naphthyridine, l-amino- 3-( 3,4-methylenedioxyphenyl )-2,7-naphthyridine,l-amino-3'(2-chlorophenyl)-2,7-naphthyridine, l-amino-3-( 3-chlorophenyl)-2,7-naphthyridine, lamino-3-(4-chlorphenyl)-2,7-naphthyridine, 1amino- 3-( 2trifluoromethylphenyl )-2,7-naphthyridine, lamino-3-(3-trifluoromethylphenyl )-2,7-naphthyridine, l-amino- 3-(4-trifluoromethylphenyl )-2,7-naphthyridine,l-amino-3-(a-naphthyl)QJ-naphthyridine, 1- amino-3-(B-naphthyl)-2,7-naphthyridine, l-amino-3- (2-chlorobenzyl )2,7-naphthyridine,1-amino-3-( 3- chlorobenzyl )-2,7-naphthyridine, l-amino-3-( 4-chlorobenzyl )-2,7-naphthyridine, l-amino-3-( 2-methylbenzyl)-2,7-naphthyridine, l-amino-3-( 3-methylbenzyl)-2,7-naphthyridine, l-amino-3-(4-methylbenzyl)2,7-naphthyridine, l-amino-3-(4- methoxybenzyl)-2,7-naphthyridine, l-amino- 3-( 2- thienyl )-2,7-naphthyridine,l-amino-3-( 2-thienylmethyl)-2,7-naphthyridine,l-amino-3-(3-thienylmethyl)- 2,7-naphthyridine,l-amino-3-(2-furyl)-2,7-naphthyridine,1-amino-3-cyclobutyl-2,7-naphthyridine,lamino-3-cyclopentyl-2,7-naphthyridine, l-amino-3-cyclohexyl-2,7-naphthyridine, l-amino-3-( 2- pyrimidinyl )-2,7naphthyridine, l-amino-3-( 2- pyrazinyl )-2,7-naphthyridine.

Similarly, by substituting the 3-cyano-4-methylpyridine reactant withequivalent quantities of 3-cyano-4- ethylpyridine,3-cyano-4-benzylpyridine, 3-cyano-4- phenethylpyridine and bysubstantially following the foregoing reaction procedure there isproduced 1- amino-3,4-dimethyl-2,7-naphthyridine, l-amino-3-methyl-4-phenyl-2,7-naphthyridine, l-amino-3-methyl-4-benzyl-2,7-naphthyridine, respectively. Similarly, in each of thosereactions wherein the 3-cyano-4-methylpyridine has been substituted withanother 3-cyano-4- substituted pyridine the acetonitrile reactant mayalso be substituted with the forementioned nitriles and by substantiallyfollowing the procedure described in the example, there is produced theappropriate l-amino-3 and 4-substituted 2,5-naphthyridine.

Preparation of l,7-naphthyridine EXAMPLE Vll 8-Amino-2-(3-methyl-2-pyridyl )-l ,7-naphthyridine To 5.9 g. of2-cyano-3-methylpyridine dissolved in 30 mls. ufdimethylformamidegradually minutes) add 6.7 g. of potassium t-butoxide at about 5C.Maintain the reaction mixture at 5C for 4-6 hours and quench thereaction mixture in ice water. Collect the crystalline precipitate andrecrystallize from toluene obtaining 3.7 g. of8-amino-2-(3-methyl-2-pyridyl)-l.7-naphthyridine, m.p. l-l7 1C.

EXAMPLE Vlll 8-Amino-2-( 3-ethyl-2-pyridyl)-3-methyll ,7-naphthyridineTo 6.3 g. of 2-cyano-3-ethylpyridine (prepared from 3-ethylpyridine bythe method described for the preparation of 2cyano-6-methylpyridine from2-methylpyridine in Organic Synthesis, Vol. 42, p. 30. The 2-cyano-3-ethylpyridine is separated from the 6-cyano and 4- cyano isomers byfractional crystallization on from ZB-ethanol or isopropanol) dissolvedin 30 mls. of dimethylformamide. gradually add 6.7 g. of potassiumt-butoxide at about 5C over a period of 20 minutes. Maintain thereaction mixture at 5C for another 4-6 hours and then quench thereaction mixture in ice water. Collect the crystalline precipitate andrecrystallize from toluene to yield 8-amino-2-(3-ethyl-2- pyridyl)-3methyll ,7-naphthyridine.

In a sim lar manner by substituting the 2-cyano-3- methyl-pyridine withequivalent quantities of 2-cyano- 3-benzylpyridine,2cyano-3-phenethylpyridine and 2-cyano-3-phenylpropylpyridine and bysubstantially following the procedure of this example there is produced8-amino-2-( 3benzyl-2-pyridyl l-3-phenyll ,7- naphthyridine,8-amino-2-(3-phenethyl-2-pyridyl)-3- benzyll ,7-naphthyridine,8-amino-2-( 3phenylpropyl- 2-pyridyl )-3-phenethyll ,7-naphthyridine,respectively. Similarly, in those instances wherein it is desired toproduce those compounds bearing substituents on the pyridyl, phenyl andbenzyl moieties of the foregoing then, as expected, the appropriatelysubstituted starting reactants are then similarly reacted.

EXAMPLE [X 8-Amino-2-( 3-methyl-2-pyridyl l ,7-naphthyridine To asuspension of sodamide (prepared from 0.23 g. of sodium) in 200 ml. ofliquid ammonia gradually add 5.9 g. of 2-cyano-3-methylpyridine. Agitatethe reaction mixture for 4 hours, add 6 g. of ammonium chloride and,using steam bath temperatures, evaporate off the ammonia. Add sufficientwater to dissolve the inorganic material and filter the remainingprecipitate which is recrystallized from toluene to give 8-amino-2-(3-methyl-2-pyridyl l ,7-naphthyridine, m.p. l70l7lC.

EXAMPLE X 8-Amino-2-(3-methyl-2-pyridyl)-1,7-naphthyridine To asuspension in ether of lithium diisopropylamide (prepared from 02 molesof lithium, 0.] moles of brombenzene and 0.l moles of diisopropylamine)add, in a dropwise fashion, at 2535C, an ether solution containing 0.]mole of 2-cyano-3-methylpyridine. Reflux the reaction mixture for 7hours. and pour the resulting mixture into ice water. Filter theprecipitated 8-amino-2-(3-methyl-2-pyridyl)-1,7-naphthyridine andrecrystallize the product from toluene.

EXAMPLE Xl 8-Amino'2-methyl-1,7-naphthyridine To 6.7 g. of potassiumt-butoxide in dimethylformamide at 05C add, in a portionwise fashion,5.9 g. of 2-cyano-3-methylpyridine and stir the reaction mixture for 1hour. Add, in a portionwise fashion, [0.2 g. of

acetonitrile and stir the reaction mixture at 05C for 48 hours. Quenchthe reaction in ice water. filter the methylbenzylcyanide.4-methoxybenzylcyanide, 2- cyanothiophene, Z-thiopheneacetonitrile,3-thiopheneacetonitrile, 2cyanofuran, cyclobutylcyanide,

cyclopentylcyanide, cyclohexylcyanide, 2- cyanopyrimidine,S-cyanopyrimidine, 2-cyanopyrazine and by substantially following theforegoing reaction procedure there is produced 8amino-2-phenyl-l,7-naphthyridine, S-amino-Z-benzyl-l ,7-naphthyridine, S-amino-Z-phenethyll,7-naphthyridine, 8-amino-2- ethyl-1,7-naphthyridine,8-amino-2-(2-pyridyl )-l ,7- naphthyridine. 8-amino-2-( 3-pyridyl l,7-naphthyridine 8-amino-2-( 4-pyridyl l ,7-naphthyridine, 8- amino-2-(2-methoxyphenyl)- l ,7-naphthyridine, 8- amino-2-(3-methoxyphenyl)- l ,7-naphthyridine, 8 amino-2-(4-methoxyphenyl)-1 ,7-naphthyridine, 8

amino-2-( 2.3-dimeth0xyphenyl )-l ,7naphthyridine, S-amino- 2-(2,6-dimethoxyphenyl l .7-naphthyridine, 8-amino-2(3.4-methylenedioxyphenyl l ,7-naphthyridine, 8-amino-2-( 2-ch1or0phenyll ,7-naphthyridine, 8-amino-2-(3-chlorphenyl)-1,7-naphthyridine, 8-amino-2-(4-chlorphenyl )l ,7-naphthyridine, 8-amino-2-(2-trifluoromethylphenyl)l ,7-naphthyridine 8- amino-2-(3trifluoromethylphenyl)-l ,7-naphthyridine,8-amino-2-(4-trifluoromethylphenyl l ,7-naphthyridine,8-amino-2-(a-naphthyD-l,7-naphthyridine, 8- amino-2-(B-naphthyl l,7naphthyridine, 8-amino-2- (2-chlorobenzyl l ,7-naphthyridine,8-amino-2-( 3- chlorobenzyl )-l ,7-naphthyridine, 8-amino-2-( 4-chlorobenzyl l ,7-naphthyridine, 8-amino-2-( 2- methylbenzyl l,7-naphthyridine, 8-amino-2-( 3- methylbenzyl l ,7-naphthyridine,8amino-2-(4- methylbenzyl l ,7-naphthyridine, 8-amino-2-( 4-methoxybenzyD- l ,7-naphthyridine, 8-amino-2-( 2- thienyl )-l,7-naphthyridine, 8-amino-2-(2-thieny1methyl)- l ,7-naphthyridine,8-amino-2-( 3-thienylmethyl)- 1,7-naphthyridine, 8-amino-2-( 2-furyl l,7-naphthyridine, 8 -amino-2-cyclobutyl-l,7-naphthyridine, 8-amino-Z-cyclopentyl-l ,7-naphthyridine, 8-amino-2- cyclohexyll,7-naphthyridine, 8-amino-2-( 2- pyrimidinyl l ,7-naphthyridine,8-amino-2-( 3- pyrimidinyl l ,7-naphthyridine, 8-amino-2-( 2- pyrazinyl)-l ,7-naphthyridine.

Similarly, by substituting the 2-cyano-3-methylpyridine reactant withequivalent quantities of 2-cyano-3- ethylpyridine,2-cyano-3-benzylpyridine, 2-cyano-3- phenethylpyridine and bysubstantially following the foregoing reaction procedure there isproduced 8- amino the dimethyl-] ,7-naphthyridine, 8-amino-2-methyl-3-phenyll ,7-naphthyridine, 8-amino-2-methyl-3-benzyl-L7-naphthyridine, respectively. Similarly, in each of thosereactions wherein reactions 2-cyano-3- methylpyridine has beensubstituted with another 2 cyano-3-substituted pyridine the acetonitrilereactant may also be substituted with the aforementioned nitriles and bysubstantially following the procedure described in the example, there isproduced the appropriate 8-amino-2 and 3-substituted 1,7-naphthyridine.

The compounds of this invention are useful as antifungal, andantibacterial agents. In general, the potency of these compounds againsta variety of bacteria and fungi by standard and conventional techniquessuch as with the use of standard disc assays. In general, the compoundsare dissolved in ().lN HCl and discs are dipped in appropriateconcentrations to provide discs containing 200 or 20 mcgJdisc. Bacteriawere grown on nutrient agar, and were incubated at 37C for 24 hours;yeasts were grown on Sabourauds agar and were incubated at 27C for 48hours; Triclwpliyron was grown on Mycosel agar and was incubated at 27Cfor 4 days prior to measurement of inhibition zones. Typical of theresults of the anti-bacterial and anti-fungal effects of the compoundsof this invention are summarized by the results of 8-amino-2-(3-methyl-2-pyridyl)- 1.7-naphthyridine in Table 1. Tube dilution tests,using conventional techniques, are used to determine further in vitropotency of the compounds of this invention. Typical results arerepresented by the data of Table II.

Table 1 Disc Testing of R-amino-2-( 3mcthyl-2-pyridyl] l 7- napthyridincInhibition Zone in mm 8-amino-2-(3-methyl-2- pyridylJ-l .7-naphthyridineOrganisms 200 mcg 20 mcg Staphylococcus aureus 2U9P 40 I Streptococcuspyrogencs C 27 (J Escherichia coli 30 0 Pseudumonas acruginosa 30 0Salmonella schottmuelleri 30 t Candida alhicans 404 I2 0 Candidaalbicans 420 30 0 Candida albicans 406 0 0 Candida albicans [203i 0 0Candida albicans 400 I6 0 Candida albicans 402 l6 0 Candida albicans 403U U Candida albicans 4| l 1 U Saccharomyccs cerevisiae 20 U Trichophytonmentagrophytes 40 Bacteria on nutrient agar, yeasts on Sabourauds agarand Trichophytun on Mycosel agar.

Table I] In Vitro Activity of 8amino-23-methyl-2-pyridyl)-l.7naphthyridine by Tube DilutionS-aminoJ-(Ii-methyl-Z- Bacteria in yeast beef brothv fungi in Sahouraudsdextrose broth.

The compounds contemplated as falling within for mula l are basic incharacter and form acid addition salts. These salts sometimes increasesolubility and lend themselves better to formulation than do the freebases. Accordingly the pharmaceutically acceptable acid addition saltsof the free bases are contemplated as being within the concept in itscomposition aspect. Such salts include those derived from maleic,salicylic, succinic, methyl sulfonic, tartaric, citric, hydrochloric,hydrobromic, sulfuric, phosphoric and the like, and are prepared bystandard and well-known techniques.

In their function as therapeutically useful compounds, it isadvantageous to administer the compounds to the host animal in admixturewith an acceptable pharmaceutical carrier suitable for enteral orparenteral administration, said carrier constituting a major portion ofthe admixture. Such preparations may be in such forms as, for example,tablets, capsules and suppositories, or in liquid forms, as for example,elixirs, emulsions, sprays and injectables. In the formulation ofpharmaceutical preparations there can be employed such substances whichdo not react with the active substance, as, for example, water, gelatin,lactose, starches, magnesium stearate, talc, vegetable oils, benzylalcohols, gums, polyalkylene glycols, petroleum jelly and the like.

The active ingredient of such pharmaceutical preparations is preferablypresent in the preparation in such proportions by weight that theproportion by weight of the active ingredient to be administered liesbetween 0.1% and 50%.

Representative embodiments of the formulations containing thecompositions of this invention are as follows:

I TABLET FORMULATIONS Procedure The 8-amino-2(3-methyl-2pyridyl)-l,7-naphthyridine is mixed with the citric acid, lactose, dicalciumphosphate, pluronic and sodium lauryl sulfate. The above mixture isscreened through a No. 60 screen and damp granulated with an alcoholicsolution consisting of polyvinylpyrrolidone. Carbowax 1500 and 6000. Addadditional alcohol, if necessary, to bring powders to a pasty mass. Addcorn starch and continue mixing until uniform granules are formed. Passthrough a No. 10 screen, tray and dry in oven at l00C for 12-14 hours.Reduce dried granulation through a No. 16 screen add sodium laurylsulfate and magnesium sulfate, mix and compress into desired shape on atablet machine.

Coating The above cores are treated with a lacquer and dusted with talcto prevent moisture adsorption. Sub-coat layers are added to round outthe core.

14 A sufficient number of lacquer coats are applied to make the coreenteric. Additional sub-coats and smoothing coats are applied tocompletely round out and smooth the tablet. Color coats are applieduntil desired shade is obtained. After drying the coated tablets arepolished to give the tablets an even gloss.

II CAPSULE FORMULATIONS A.Formula Mg./capsule 8-Amino-2-(3-mcthyl-2-pyridyl l,7-naphthyridine l 00.00 Citric Acid l.00 Pluronic,F 68 4000 Sodium Lauryl Sulfate 20.00 Lactose 238.00 Magnesium stcarateL00 Procedure Mix together 8-amino-2-(3-methyl-2-pyridyl)-l,7-naphthyridine, citric acid, pluronic, sodium lauryl sulfateand lactose. Pass through a No. screen. Add magnesium stearate, mix andencapsulate into the proper size 2-piece gelatin capsule.

B.Formula Mg./capsule 8-Amino-2-(3-methyl-2-pyridyl]- l,7-naphthyridinc100.0 Dried aluminum hydroxide gel I000 Citric acid 1.0 Pluronic, F-6850.0 Sodium lauryl sulfate 25.0 Lactose 222.0 Magnesium stearatc 2.0500.0

Procedure Mix together 8-amino-2-(3-methyl-2-pyridyl)-1,7-naphthyridine, citric acid, pluronic, sodium lauryl sulfateand lactose. Pass through a No. 80 screen. Add magnesium stearate, mixand encapsulate into the proper size Z-piece gelatin capsule adding thedried aluminum hydroxide gel to the mixture before screening.

Ill ORAL SUSPENSION Purified water, USP. to make 5 ml.

Method of Manufacture Dissolve the sodium saccharin, sodium benzoate,standard granulated sugar and sorbitol solution in approximately 80% ofthe required amount of water. Disperse the Veegum in approximately 5% ofthe required amount of water and add the dispersion to the previouslyprepared syrup. Prepare a slurry of the 8-amino-2-(3-methyl-2- pyridyD-l,7-naphthyridine with approximately 10% of the required amount of waterand pass through a suitable colloid mill until free of grittiness. Addthe milled active slurry to the batch. Dissolve the menthol and flavorin the alcohol and add the resulting solution to the batch. Addsufficient purified water to bring the batch to total volume. Agitateuntil uniform.

Additionally, the compounds of this invention are useful as antiobesityagents at dosage ranges of about lO-SO m.p.k. per day. In this end-usecharacteristic the compounds have demonstrated the ability to inhibitlipogenesis in adipose tissue as determined by adminis tration of tracerdoses of radio-glucose together with an oral glucose level to male ratsand the radioactivity in the epididymal fat pad is measured as an indexof lipid synthesis. The test compound is administered one hour prior tothe administration of the glucose. The active compounds decrease theradioactivity in the fat pad. Those compounds which are active in thistest procedure, i.e. have the ability to decrease epididymal fat pad andbody weights in male rats. are very useful as antiobesity agents.

Of particular interest in the class of naphthyridines of this inventionare those compounds having in their 6-position a pyridyl radical. Ofparticular interest are 8-amino-2-( B-methyl-Z-pyridyl l,7-naphthyridine, 8- amino-2-( 3-methyl-4-pyridyl ,7-naphthyridine and8N-methylamino-6( S-methyI-Z-pyridyl l ,7-naphthyridine.

In their use as antiobesity agents the compounds are administered inadmixture with suitable pharmaceutical carriers such as those describedhereinabove.

16 We Claim: 1. A l 7-naphthyridine compound of the structural formula:

1. A 1,7-NAPHTHYRIDINE COMPOUND OF THE STRUCTURAL FORMULA:
 2. A compoundof claim 1 wherein R2 is hydrogen.
 3. A compound of claim 1 wherein R2is lower alkyl.
 4. A compound of claim 1 wherein R2 is phenyl.
 5. Acompound of claim 1 wherein R2 is benzyl.
 6. A compound of claim 1wherein R2 is phenethyl.
 7. A compound of claim 1, said compound being8-amino-2-(3-methyl-2-pyridyl)-1,7-naphthyridine.